ARIA: A Phase 1b/2, Open-label, Multi Cohort Trial of Tazemetostat in Combination With Various Treatments in Subjects With Relapsed or Refractory Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 3
- 主要终点
- Phase 2: Objective Response Rate (ORR)
研究概览
简要总结
This trial will study how safely the tazemetostat works with other therapies in various hematological malignancies. Hematologic malignancies are cancers that most often begin in the bone marrow or lymph nodes where blood precursors are produced.
They are often called blood cancers and fall into three categories: leukemia, lymphoma and myeloma.
Tazemetostat has been found to be a safe and effective drug that works in patients with follicular lymphoma where the disease has come back after treatment (known as relapsed) and when other treatment no longer works (known as refractory).
Combining tazemetostat with other treatments may work better in treating patients with hematological malignancies and may improve disease response and durability of response.
详细描述
This phase 1b/2 trial studies how safely the EZH2 inhibitor tazemetostat works with other therapies in various hematological malignancies. Tazemetostat has been found to be a safe and effective drug that works in patients with relapsed refractory (R/R) follicular lymphoma. Giving tazemetostat in combination with other treatments may work better in treating patients with hematological malignancies and may improve disease response and durability of response.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 for Phase 1b and status 0 to 2 for Phase 2
- •Must have documented relapsed, refractory, or progressive disease after 2 lines of treatment with systemic therapy
- •Measurable disease
- •Demonstrate adequate organ function
- •Negative test results for acute or chronic hepatitis B virus (HBV) infection, hepatitis C virus (HCV) and human immunodeficiency virus
- •No ongoing clinically significant reactions to prior anticancer treatments
- •Willingness to follow pregnancy precautions and register into the mandatory REMS program in lenalidomide and pomalizdomide arms
排除标准
- •Presence or history of central nervous system involvement by lymphoma
- •Less than minimum washout period of prior anticancer therapy as specified by the protocol
- •Prior allogeneic haematopoietic stem cell transplantation
- •History of solid organ transplant
- •Major surgery within 4 weeks of the start of study drug.
- •Significant cardiac or cardiovascular impairment as specified by protocol
- •Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat
- •History of any bleeding disorder, peptic ulcer disease, or significant bleeding within the last 1 month prior to enrollment
- •Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition
- •Patients with known active infection, or reactivation of a latent infection, as specified by the protocol
- •Known sensitivity or allergy to the study medications
- •Unwilling to refrain from eating or drinking grapefruit juice, Seville oranges, and grapefruits while on study
- •Prior exposure to tazemetostat
- •Any condition that places the subject at unacceptable risk if he/she were to participate in the study or that confounds the ability to interpret data from the study.
- •Prior history of myeloid malignancies or T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL)
- •For patients with DLBCL in Arm 1 (tazemetostat plus tafasitamab plus lenalidomide) or Arm 2 (tazemetostat plus lenalidomide):
- •Prior exposure to lenalidomide
- •For patients with MCL in Arm 3 (tazemetostat plus acalabrutinib):
- •Prior exposure to a BTKi
- •Medical condition that would make treatment with a BTKi not reasonable (e.g. allergy to BTKi or mutations known not to respond to BTKi treatment or subjects unable to be transitioned off of proton pump inhibitors)
- •For patients with MM in Arm 4:
- •Prior exposure to pomalidomide
- •Untreated or impending spinal cord compression in subjects
- •For patients with FL in Arm 5:
- •Grade 3b, mixed histology, or FL that has histologically transformed to DLBCL.
- •History of significant neurological disorders, hemophagocytic lymphohistiocytosis (HLH), chronic active Epstein-Barr virus (EBV) infection, progressive multifocal leukoencephalopathy (PML), lung disease (ILD), drug-induced pneumonitis, autoimmune pneumonitis, and/or history of severe autoimmune disease
研究组 & 干预措施
Arm 1-Tazemetostat plus tafasitamab-cxix (CD19 Ab)/lenalidomide
Participants with R/R, diffuse large B-cell lymphoma (DLBCL) will receive tazemetostat, tafasitamab, and lenalidomide for approximately 1 year.
After approximately 1 year, participants will receive tazemetostat and tafasitamab.
干预措施: Tazemetostat (Drug)
Arm 1-Tazemetostat plus tafasitamab-cxix (CD19 Ab)/lenalidomide
Participants with R/R, diffuse large B-cell lymphoma (DLBCL) will receive tazemetostat, tafasitamab, and lenalidomide for approximately 1 year.
After approximately 1 year, participants will receive tazemetostat and tafasitamab.
干预措施: Tafasitamab (Drug)
Arm 1-Tazemetostat plus tafasitamab-cxix (CD19 Ab)/lenalidomide
Participants with R/R, diffuse large B-cell lymphoma (DLBCL) will receive tazemetostat, tafasitamab, and lenalidomide for approximately 1 year.
After approximately 1 year, participants will receive tazemetostat and tafasitamab.
干预措施: Lenalidomide (Drug)
Arm 2-Tazemetostat plus lenalidomide
Participants with R/R DLBCL will receive tazemetostat and lenalidomide for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone.
干预措施: Tazemetostat (Drug)
Arm 2-Tazemetostat plus lenalidomide
Participants with R/R DLBCL will receive tazemetostat and lenalidomide for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone.
干预措施: Lenalidomide (Drug)
Arm 3- Tazemetostat plus BTKi (acalabrutinib)
Participants with R/R mantle cell lymphomawill (MCL) will receive tazemetostat and acalabrutinib for the entire study.
干预措施: Tazemetostat (Drug)
Arm 3- Tazemetostat plus BTKi (acalabrutinib)
Participants with R/R mantle cell lymphomawill (MCL) will receive tazemetostat and acalabrutinib for the entire study.
干预措施: Acalabrutinib (Drug)
Arm 3- Tazemetostat plus BTKi (acalabrutinib)
Participants with R/R mantle cell lymphomawill (MCL) will receive tazemetostat and acalabrutinib for the entire study.
干预措施: Hyaluronidase-Fihj (Drug)
Arm 4-Tazemetostat plus CD38 mAbPD (daratumumab/pomalidomide/dexamethasone)
Participants with R/R multiple myelomawill (MM) will receive tazemetostat, daratumumab, pomalidomide, and dexamethasone for the entire study.
Daratumumab may be given intravenously or subcutaneously during this study.
干预措施: Tazemetostat (Drug)
Arm 4-Tazemetostat plus CD38 mAbPD (daratumumab/pomalidomide/dexamethasone)
Participants with R/R multiple myelomawill (MM) will receive tazemetostat, daratumumab, pomalidomide, and dexamethasone for the entire study.
Daratumumab may be given intravenously or subcutaneously during this study.
干预措施: Daratumumab (Intravenously) (Drug)
Arm 4-Tazemetostat plus CD38 mAbPD (daratumumab/pomalidomide/dexamethasone)
Participants with R/R multiple myelomawill (MM) will receive tazemetostat, daratumumab, pomalidomide, and dexamethasone for the entire study.
Daratumumab may be given intravenously or subcutaneously during this study.
干预措施: Daratumumab (Subcutaneously) (Drug)
Arm 4-Tazemetostat plus CD38 mAbPD (daratumumab/pomalidomide/dexamethasone)
Participants with R/R multiple myelomawill (MM) will receive tazemetostat, daratumumab, pomalidomide, and dexamethasone for the entire study.
Daratumumab may be given intravenously or subcutaneously during this study.
干预措施: Pomalidomide (Drug)
Arm 4-Tazemetostat plus CD38 mAbPD (daratumumab/pomalidomide/dexamethasone)
Participants with R/R multiple myelomawill (MM) will receive tazemetostat, daratumumab, pomalidomide, and dexamethasone for the entire study.
Daratumumab may be given intravenously or subcutaneously during this study.
干预措施: Dexamethasone 20mg (Drug)
Arm 5- Tazemetostat plus CD20/CD3 BsAb (mosunetuzumab)
Participants with R/R follicular lymphoma will receive tazemetostat and mosunetuzumab for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone.
干预措施: Tazemetostat (Drug)
Arm 5- Tazemetostat plus CD20/CD3 BsAb (mosunetuzumab)
Participants with R/R follicular lymphoma will receive tazemetostat and mosunetuzumab for approximately 1 year. After approximately 1 year, participants will receive tazemetostat alone.
干预措施: Mosunetuzumab (Drug)
结局指标
主要结局
Phase 2: Objective Response Rate (ORR)
时间窗: Time from the date of first dose of study drug to the time of response, assessed up to 24 months.
Overall response rate is defined as proportion of participants with a best response of at least partial remission (including partial remission and complete remission for participants with non-Hodgkin lymphoma in Arms 1, 2, 3, or 5 or partial remission, complete remission, stringent complete response, or very good partial response).
Phase 1b: Recommended Phase 2 Dose (RP2D) of tazemetostat in combination with each partner drug
时间窗: Evaluated for DLTs during the first 28-day cycle. The RP2D for Phase 2 for each arm will be selected at the end of that arm's experience in Phase 1b
The safety and tolerability of tazemetostat in combination with each partner drug in participants with R/R malignancies will be evaluated. RP2D of tazemetostat for further evaluation in phase 2 will be selected as assessed by the occurrence of treatment-emergent dose-limiting toxicities (DLTs) and adverse events (AEs).
次要结局
- Phase 2: Progression Free Survival (PFS)(Up to 24 months.)
- Time to response (TTR)(Up to 24 months)
- Phase 2: Duration of Response (DOR)(Up to 24 months)
- Percentage of participants with Treatment Emergent Adverse Event (TEAEs)(Up to 24 months)
- Phase 2: Disease control rate (DCR)(Up to 24 months)
- Phase 2: Overall Survival (OS)(Up to 24 months)
- Time to next treatment (TTNT)(Up to 24 months)
- Percentage of participants with clinically significant changes in laboratory parameters(Up to 24 months)